Gelatin compositions

ABSTRACT

The invention concerns Gelatin compositions for the use in pharmaceutical, veterinary, food, cosmetic or other products like films for wrapping food, aspics or jellies, preferably for predosed formulations like soft or hard gelatin capsules wherein the gelatin used is of non-bovine and non-pig origin and preferably derived from fish, poultry or plant sources. Especially preferred are film compositions for hard gelatine capsules prepared from fish gelatin.

[0001] The invention concerns gelatin compositions for the use inpharmaceutical, veterinary, food, cosmetic or other products like filmsfor wrapping food, aspics or jellies, preferably for predosedformulations like soft or hard gelatin capsules wherein the gelatin usedis of non-bovine and non-pig origin and preferably derived from fish,poultry or plant sources. Especially preferred are film compositions forhard gelatine capsules prepared from fish gelatin.

[0002] A second embodiment of the invention is the use of the filmcomposition for the manufacturing of hard gelatin capsules byconventional dip moulding processes.

[0003] The gelatin used for hard gelatin capsules is traditionallyproduced by extraction from collagen containing mammalian tissues,particularly such as pig skin and bovine bone. Gelatin from pig andbovine origin are preferably used for their gelling, film forming andsurface-active properties. The manufacture of hard gelatin capsules bydip moulding process exploits fully its gelling and film formingabilities. Such capsules are manufactured by dipping mould pins into ahot solution of gelatin, removing the pins from the gelatin solution,allowing the gelatin solution attached on pins to set by cooling, dryingand stripping the so-formed shells from the pins. The setting of thesolution on the mould pins after dipping is the critical step to obtainan uniform thickness of the capsule shell.

[0004] Fish collagen is a further source of gelatin. However, it haslong been known that gelatin derived from fish collagen lacks much ofthe gelling and setting ability of mammalian gelatins which limits thefish gelatin application. It is only applicable for products where ahigh viscosity of the solution without gel formation is desired, forexample, in glue or food manufacturing. In the field of predosedpharmaceuticals, the fish gelatin can be used for micro-encapsulation(WO 9620612) or for the production of soft capsules where the gellingand setting ability is not a critical parameter in the manufacturingprocess.

[0005] A. N. Fraga et al. describe in J. Polym. Mater. 5 (1988) 49-55the mechanical properties from fish Gelatins as a brittle behaviorcharacteristic of a glassy material at normal temperatures. Such abrittleness is very undesired property for a gelatin capsule.

[0006] Norland Products Inc. describe in Research Disclosure 1987, 788that water solutions of fish gelatin remain liquid down to 10° C.,wheras water solutions of animal gelatin must be heated to temperaturesover 30° C. to remain liquid. This behavior of fish gelatin will notallow the use in the conventional dip moulding process at conventionaltemperatures because of ist to low gelling temperature.

[0007] B. Leuenberger describes in Food Hydrocolloids 1991, 353-361viscosity and gelation properties of different mammalian and fishgelatins with the conclusion that fish gelatin may be usefull inapplications where high solution viscosity without gel formation isdesired.

[0008] Surprisingly it has been found that fish gelatin can be used forthe production of conventional Gelatins with conventional properties byadding a setting system to the aqueous fish gelatin solution.

[0009] The problem of the invention is therefore the provision ofcompositions for the production of Gelatins for the use inpharmaceutical, veterinary, food, cosmetic or other products like filmsfor wrapping food, aspics or jellies, preferably for predosedformulations like soft or hard gelatin capsules wherein the gelatin usedis of non-bovine and non-pig origin and preferably derived from fish,poultry or plant sources, and wherein a setting system is added to theaqueous gelatin solution. Especially preferred are film compositions forhard gelatine capsules prepared from fish gelatin.

[0010] Surprisingly this is achieved by the addition of a setting systemand this allows the use of a wide range of gelatins from other sourcesthan pigs or cattle for gelatin products for human consumption avoidingethical and cultural problems.

[0011] The addition of a setting system to the aqueous gelatin solutionenables the adaption of specific and desired gelling properties also togelatin solutions with normally insufficient gelling behavior,especially for the production of hard gelatin capsules. For theproduction of such capsules it is extremly important that the filmforming gelation solution remaining on the mould pins after dipping isprohibited from flowing down the pins. Otherwise the obtained film willnot have the desired uniform thickness.

[0012] Consequently hard gelatin capsules from other gelatin sources canbe produced with the same equipment as for conventional hard gelatincapsules in the range of same process conditions. Furthermore capsulesproduced from compositions of the instant invention have the samedimensional specifications and allow the use of the existing fillingmachinery and do not require specific and new equipment for the capsuleusers. The capsules produced from the gelatin compositions of theinvention have also acceptable mechanical and dissolution properties.

[0013] The gelatin concentration in the dipping solution is in a rangeof 10 to 60%, preferably in the range of 20 to 40% by weight.

[0014] The setting system consist of a hydrocolloid or mixtures ofhydrocolloids and cations and may contain in addition sequesteringagents.

[0015] Suitable hydrocolloides or mixtures producing synergisticproperties may be selected from natural seaweeds, natural seed gums,natural plant exudates, natural fruit extracts, biosynthetic gums,bio-synthetic processed starch or cellulosic materials, preferred arethe polysaccharides.

[0016] The preferred polysaccharides are alginates, agar gum, guar gum,locust bean gum (carob), carrageenan, tara gum, gum arabic, ghatti gum,Khaya grandifolia gum, tragacanth gum, karaya gum, pectin, arabian(araban), xanthan, gellan, starch, Konjac mannan, galactomannan,funoran, and other exocellular polysaccharides. Preferred areexocellular polysaccharides.

[0017] The preferred exocellular polysaccharides are xanthan, acetan,gellan, welan, rhamsan, furcelleran, succinoglycan, scleroglycan,schizophyllan, tamarind gum, curdlan, pullulan, dextran. Preferred arekappa-carrageenan or gellan gum or combinations like xanthan with locustbean gum or xanthan with konjac mannan. The amount of the hydrocolloidis preferably in the range of 0.01 to 5% by weight and especiallypreferred 0.03 to 1.0% in the aqueous gelatin solution.

[0018] The cations are preferably selected from, K⁺, Na⁺, Li⁺, NH₄ ⁺,Ca⁺⁺ or Mg⁺⁺, for kappa-carrageenan are preferred K⁺, NH₄ ⁺ or Ca⁺⁺.

[0019] The preferred sequestering agents are ethylenediaminetetraaceticacid, acetic acid, boric acid, citric acid, edetic acid, gluconic acid,lactic acid, phosphoric acid, tartaric acid or salts thereof,methaphosphates, dihydroxyethylglycine, lecithin or beta cyclodextrinand combinations thereof. Especially preferred isethylenediaminetetraacetic acid or salts thereof or citric acid or saltsthereof. The amount is preferably 0.01 to 3%, especially 0.1 to 2% byweight of the dipping solution.

[0020] Among the setting systems mentioned above, the systems ofkappa-carrageenan with cation and gellan gum with cation arespecifically preferred. They produce high gel strength at lowconcentrations and have excellent compatibility with gelatin.

[0021] The Gelatins produced from the dipping solutions as describedwill consequently by a water content of 7 to 17% by weight contain byweight 83 to 93% gelatin, 0.01 to 10%, preferably 0.1 to 3%hydrocolloids, 0.001 to 3%, preferably 0.01 to 1% cations depending onthe hydrocolloids used, and optional 0.001 to 3%, preferably 0.01 to 1%sequestering agents.

[0022] Capsules or films with the inventive gelatin composition may bemanufactured with conventional machines by the conventional processeslike extrusion moulding, injection moulding, casting or dip moulding.

[0023] The inventive gelatin composition may contain additionallyacceptable plasticizers in an range from about 0 to 40% based upon theweight of the gelatin. Suitable plasticizers are polyethylene glycol,glycerol, sorbitol, sucrose, corn syryp, fructose, dioctyl-sodiumsulfosuccinate, triethyl citrate, tributyl citrate, 1,2-propylenglycol,mono-, di- or triacetates of glycerol, natural gums or the like as wellas mixtures thereof.

[0024] The inventive gelatin composition may contain in a further aspectadditionally pharmaceutically or food acceptable coloring agents in therange of from 0 to 10% based upon the weight of the gelatin. Thecoloring agents may be selected from azo-, quinophthalone-,triphenylmethane-, xanthene- or indigoid dyes, iron oxides orhydroxides, titanium dioxide or natural dyes or mixtures thereof.Examples are patent blue V, acid brilliant green BS, red 2G, azorubine,ponceau 4R, amaranth, D+C red 33, D+C red 22, D+C red 26, D+C red 28,D+C yellow 10, yellow 2 G, FD+C yellow 5, FD+C yellow 6, FD+C red 3,FD+C red 40, FD+C blue 1, FD+C blue 2, FD+C green 3, brilliant black BN,carbon black, iron oxide black, iron oxide red, iron oxide yellow,titanium dioxide, riboflavin, carotenes, anthocyanines, turmeric,cochineal extract, clorophyllin, canthaxanthin, caramel, or betanin.

[0025] The shaped gelatin composition of the invention or the finalproduct therof may be coated with a suitable coating agent likecellulose acetate phthalate, polyvinyl acetate phthalate, methacrylicacid gelatins, hypromellose phthalate, hydroxypropylmethyl cellulosephthalate, hydroxyalkyl methyl cellulose phthalates or mixtures thereofto provide e.g. enteric properties.

[0026] The gelatin composition of the invention may be used for theproduction of containers for providing unit dosage forms for example foragrochemicals, seeds, herbs, foodstuffs, dyestuffs, pharmaceuticals,flavoring agents and the like.

[0027] The inventive gelatin composition makes it useful for theencapsulation of caplets in a capsule, especially in a tamperproof form.The encapsulation of a caplet in a capsule is preferred processed bycold shrinking together capsule parts, which are filled with a caplet,which comprises the steps providing empty capsule parts, filling atleast one of said capsule parts with one or more caplets, putting saidcapsule parts together, and treating the combined capsule parts by coldshrinking.

[0028] The inventive gelatin composition is also useful forencapsulating and sealing the two capsule halves in a process in whichone or more layers of the composition are applied over the seam of thecap and body, or by a liquid fusion process wherein the filled capsulesare wetted with a hydroalcoholic solution that penetrates into the spacewhere the cap overlaps the body, and then dried.

[0029] A specific embodiement of the instant invention is a hard gelatincapsule from fish gelatin filled with fish oil.

[0030] The improved properties of the gelatin composition aredemonstrated by the following examples:

EXAMPLE 1

[0031] To 3.39 kg of deionised water is added 5 g of potassium acetate(0.10% by weight in the solution), followed by addition of 10 gkappa-carrageenan (0.20% by weight) under stirring at about 70° C. Whena clear solution is obtained 1.60 kg of fish gelatin (32% by weight) areadded at 60° C. under slow stirring until the gelatin is completelydissolved and the solution is defoamed.

[0032] The fish gelatin solution thus prepared is then poured into adipping dish of a pilot machine of conventional hard gelatin capsuleproduction equipment. While keeping the temperature of dipping fishgelatin solution at about 50° C., natural transparent hard fish gelatincapsules of size 1 were produced according to the conventional processwith the same dimensional specifications to the conventional hardgelatin capsules.

EXAMPLE 2

[0033] To 5 kg of fish gelatin solution at 60° C., prepared according toexample 1, are added 32.6 g of titanium dioxide previously dispersedinto a small quantity of water. After homogenising the solution, it ispoured into the dipping dish, and white opaque hard fish gelatincapsules of size 1 were produced as in the example 1.

[0034] The capsules from both examples have excellent dissolutionproperties as demonstrated in FIG. 1, showing the percentage ofacetaminophen dissolved from capsules immersed in deionised water at 37°C. (USP XXIII) as a function of dissolution time.

1. Gelatin compositions consisting of a gelatin of non-bovine andnon-pig origin and a setting system.
 2. Gelatin compositions accordingto claim 1 , wherein the gelatin is derived from fish, poultry orplants.
 3. Gelatin compositions according to claim 1 , wherein thegelatin is fish skin gelatin.
 4. Gelatin compositions according to claim1 , wherein the setting system consists of hydrocolloids and cations. 5.Gelatin compositions according to claim 1 , wherein the setting systemcontains optionally sequestering agents.
 6. Gelatin compositionsaccording to claim 1 , wherein the gelatin is contained in an amount of83 to 93% by weight by a water content of 7 to 17% by weight and thehydrocolloids are contained in an amount of 0.01 to 10%, preferably 0.1to 3% by weight and cations in an amount of 0.001 to 3%, preferably 0.01to 1% by weight.
 7. Gelatin compositions according to claim 1 , whereinthe setting system contains optionally sequestering agents in an amountof 0.001 to 3%, preferably 0.01 to 1% by weight of the composition. 8.Gelatin compositions according to claim 1 , wherein the hydrocolloids ofthe setting system are selected from polysaccharides.
 9. Gelatincompositions according to claim 1 , wherein the hydrocolloids of thesetting system are selected from alginates, agar gum, guar gum, locustbean gum (carob), carrageenan, tara gum, gum arabic, ghatti gum, Khayagrandifolia gum, tragacanth gum, karaya gum, pectin, arabian (araban),xanthan, gellan, starch, Konjac mannan, galactomannan, or funoran. 10.Gelatin compositions according to claim 1 , wherein the hydrocolloids ofthe setting system are selected from exocellular polysaccharides. 11.Gelatin compositions according to claim 1 , wherein the hydrocolloids ofthe setting system are selected from xanthan, acetan, gellan, welan,rhamsan, furcelleran, succinoglycan, scleroglycan, schizophyllan,tamarind gum, curdlan, pullulan, or dextran.
 12. Gelatin compositionsaccording to claim 1 , wherein the hydrocolloids of the setting systemare selected from gellan gum or kappa-carrageenan.
 13. Gelatincompositions according to claim 1 , wherein the optional sequesteringagent or mixture of sequestering agents of the setting system isselected from ethylenediaminetetraacetic acid, acetic acid, boric acid,citric acid, edetic acid, gluconic acid, lactic acid, phosphoric acid,tartaric acid or salts thereof, methaphosphates, dihydroxyethylglycine,lecithin or beta cyclodextrin.
 14. Gelatin compositions according toclaim 14 , wherein the sequestering agent or mixture of sequesteringagents is selected from ethylenediaminetetraacetic acid or salts thereofor citric acid or salts thereof.
 15. Gelatin compositions according toclaims 1 to 14 containing additionally plasticizers in an range fromabout 0 to 40% based upon the weight of the gelatin.
 16. Gelatincomposition according to claim 15 wherein the plasticizer or mixture ofplasticizers is selected from polyethylene glycol, glycerol, sorbitol,sucrose, corn syryp, fructose, dioctyl-sodium sulfosuccinate, triethylcitrate, tributyl citrate, 1,2-propylenglycol, mono-, di- or triacetatesof glycerol, or natural gums.
 17. Gelatin compositions according toclaims 1 to 16 containing additionally coloring agents in an range fromabout 0 to 10% based upon the weight of the cellulose ether.
 18. Gelatincompositions according to claim 17 wherein the coloring agent or mixtureof coloring agents is selected from azo-, quinophthalone-,triphenylmethane-, xanthene- or indigoid dyes, iron oxides orhydroxides, titanium dioxide or natural dyes.
 19. Gelatin compositionsaccording to claim 17 wherein the coloring agent or mixture of coloringagents is selected from patent blue V, acid brilliant green BS, red 2G,azorubine, ponceau 4R, amaranth, D+C red 33, D+C red 22, D+C red 26, D+Cred 28, D+C yellow 10, yellow 2 G, FD+C yellow 5, FD+C yellow 6, FD+Cred 3, FD+C red 40, FD+C blue 1, FD+C blue 2, FD+C green 3, or brilliantblack BN.
 20. Gelatin compositions according to claim 17 wherein thecoloring agent or mixture of coloring agents is selected from carbonblack, iron oxide black, iron oxide red, iron oxide yellow, titaniumdioxide, riboflavin, carotenes, anthocyanines, turmeric, cochinealextract, clorophyllin, canthaxanthin, caramel, or betanin. 21.Containers for unit dosage forms for agrochemicals, seeds, herbs,foodstuffs, dyestuffs, pharmaceuticals, or flavoring agents producedfrom the gelatin compositions according to claims 1 to 20 . 22.Container according to claim 21 which is a pharmaceutical capsule. 23.Containers according to claim 21 or 22 , characterized in that it has acoating.
 24. Coated container according to claim 23 wherein the coatingis selected from cellulose acetate phthalate, polyvinyl acetatephthalate, methacrylic acid gelatins, hypromellose phthalate,hydroxypropylmethyl cellulose phthalate hydroxyalkyl methyl cellulosephthalates or mixtures thereof.
 25. Caplets encapsulated in Gelatincompositions according to claims 1 to 20 .
 26. Capsules according toclaim 21 or 22 characterized in that the capsule halves are sealed withone or more layers of the gelatinic composition according to claims 1 to20 .
 27. Capsules according to claim 21 or 22 characterized in that thecapsule halves are sealed by a liquid fusion process.
 28. Capsulesaccording to claim 21 or 22 containing products derived from fish,preferred fish oil.
 29. Aqueous solutions of gelatin compositionsaccording to claims 1 to 20 for the manufacturing of gelatin capsules.30. Aqueous solutions according to claim 29 , containing gelatin in anamount of 10 to 60%, preferably 20 to 40% by weight, hydrocolloids in anamount of 0.01 to 5%, preferably 0.03 to 1.0% by weight and cations inan amount of 0.01 to 3%, preferably 0.1 to 2% by weight of the aqueoussolution.
 31. Aqueous solutions according to claim 29 or 30 , containingoptionally sequestering agents in an amount of 0.01 to 3%, preferably0.1 to 2% by weight of the aqueous solution.
 32. Use of aqueous gelatinsolutions according to claims 29 to 31 for the manufacturing of hardgelatin capsules in a dip moulding process.
 33. Manufacturing of hardgelatin capsules from aqueous gelatin solutions according to claims 29to 31 in a dip moulding process with conventional hard gelatin capsulesprocess parameters and equipment.